Body weight gain inhibitor

ABSTRACT

The invention provides a pharmaceutical agent containing a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof, which shows superior effect for the suppression of body weight gain. In addition, the present invention provides such a pharmaceutical agent as does not increase body weights of patients even if a therapeutically effective PPARγ agonistic substance is administered in the treatment of diabetes and other diseases.

This application is the National Phase filing of International PatentApplication No. PCT/JP2003/016656, filed Dec. 25, 2003.

TECHNICAL FIELD

The present invention relates to a body weight gain inhibitor,particularly an inhibitor of body weight gain induced by a PPARγagonist-like substance, which is useful for the treatment of diabetesand the like.

BACKGROUND ART

In view of the fact that becoming obese due to body weight gain is notonly undesirable for cosmetic reasons but also poses a greater risk forhealth that leads to life-style related diseases such as diabetes,hypertension, hyperlipidemia and the like; suppression of body weightgain is considered to be important for reducing the incidence oflife-style related diseases. While suppression of body weight gainnaturally requires sufficient exercise and balanced dietary habits,these alone are practically insufficient to achieve the goal and, as thesituation stands, a method of appropriately controlling the body weightis not easy to find.

On the other hand, body weight gain of patients suffering fromlife-style related diseases such as diabetes, hypertension,hyperlipidemia and the like often causes aggravation of the illness.Since body weight gain is caused not only by way of ingestion of foodbut also sometimes by the administration of therapeutic agents forlife-style related diseases, suppression of body weight gain of patientsis also significant for the treatment of life-style related diseasessuch as diabetes, hypertension, hyperlipidemia and the like.

It has been known that insulin sensitizers recognized as highly superiortherapeutic agents for diabetes (e.g., troglitazone, pioglitazone,rosiglitazone etc.) have a PPARγ agonistic activity (e.g., Journal ofPharmacology and Experimental Therapeutics, 284, 751-759 (1998)). Whilethese pharmaceutical agents are effective for the treatment of diabetes,some of them have been found to increase body weights of patients aftertheir administration (WO 93/03724, Diabetes, 47, suppl. 1, A18, No. 69,1998). Such drug-induced body weight gain is one of the effects desiredto be avoided as much as possible for patients with diabetes. This isbecause obesity causes aggravation of diabetes.

For example, JP-A 5-271228, JP-A 2001-316296 and the like describe thata compound having an angiotensin II antagonistic activity shows asuperior therapeutic effect for circulatory diseases and the like, suchas hypertension, cardiac diseases, stroke, renal diseases,arteriosclerosis and the like. In addition, JP-A 9-323940 describes thata pharmaceutical agent comprising a compound having an angiotensin IIantagonistic activity in combination with a compound having an insulinsensitizing activity and the like can markedly decrease the dose of eachactive ingredient as compared to the dose thereof used as a singleagent, which in turn can decrease expression of side effects as comparedto the use of the active ingredients as single agents, and can beadvantageously used as a prophylactic or therapeutic agent for variousangiotensin II-mediated diseases, particularly, as a prophylactic ortherapeutic agent for arterial hypertension associated witharteriosclerosis or hypertension as a complication and the like.

JP-A 2001-316296 describes obesity, which is one of themetabolic/nutritional disturbances, as a target disease of a compoundhaving an angiotensin II antagonistic activity. However, thispublication does not report on the suppression of body weight gain(particularly, body weight gain induced by a PPARγ agonist-likesubstance) by a compound having an angiotensin II antagonistic activity,irrespective of whether excess weight (including obesity) is observed.

OBJECT OF INVENTION

The present invention aims at providing a pharmaceutical agentexhibiting a superior effect on the suppression of body weight gain.

In addition, the present invention aims at providing such apharmaceutical agent as does not increase body weights of patients evenif a therapeutically effective PPARγ agonistic substance is administeredin the treatment of diabetes and other diseases.

SUMMARY OF THE INVENTION

The present inventors have first found that a compound having anangiotensin II antagonistic activity, a prodrug thereof or a saltthereof (hereinafter sometimes to be simply abbreviated as a “compoundhaving an angiotensin II antagonistic acyivity”) suppresses body weightgain, which resulted in the completion of the present invention.

Accordingly, the present invention relates to:

-   (1) a body weight gain inhibitor comprising a compound having an    angiotensin II antagonistic activity, a prodrug thereof or a salt    thereof,-   (2) the inhibitor according to the above-mentioned (1), wherein the    body weight gain occurs before reaching obesity,-   (3) the inhibitor according to the above-mentioned (1), wherein the    body weight gain is observed in a patient with obesity,-   (4) the inhibitor according to the above-mentioned (3), wherein the    obesity is associated with diabetes,-   (5) the inhibitor according to the above-mentioned (4), further    comprising a PPARγ agonist-like substance in combination,-   (6) the inhibitor according to the above-mentioned (1), wherein the    body weight gain is induced by a PPARγ agonist-like substance,-   (7) the inhibitor according to the above-mentioned (6), which    suppresses the body weight gain induced by a PPARγ agonist-like    substance to not more than about 80%,-   (8) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity is a    non-peptidic compound,-   (9) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity has an    oxygen atom in a molecule,-   (10) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity has an ether    bond or a carbonyl group in a molecule,-   (11) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity is a    compound represented by the formula (I):

wherein R¹ denotes a group which can form an anion or a group which canbe converted into the group which can form an anion, X denotes that thephenylene group and the phenyl group are bound directly or through aspacer having no more than 2 of atom chains, n denotes 1 or 2, a ring Adenotes a benzene ring optionally further having a substituent, R²denotes a group which can form an anion or a group which can beconverted into the group which can form an anion, and R³ denotes ahydrocarbon residue which may be bound via a hetero atom and which mayhave a substituent,

-   (12) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity is    2-ethoxy-1-[[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic    acid,-   (13) the inhibitor according to the above-mentioned (1), wherein the    compound having an angiotensin II antagonistic activity, or a salt    thereof is Losartan, Losartan potassium, Eprosartan, Candesartan    cilexetil, Candesartan, Valsartan, Telmisartan, Irbesartan,    Olmesartan, Olmesartan medoxomil, or Tasosartan,-   (14) a method of inhibiting a body weight gain in a mammal, which    comprises administering an effective amount of a compound having an    angiotensin II antagonistic activity, a prodrug thereof or a salt    thereof to the mammal,-   (15) use of a compound having an angiotensin II antagonistic    activity, a prodrug thereof or a salt thereof for the production of    a body weight gain inhibitor, and the like.

The angiotensin II antagonistic activity in the present invention isinhibiting binding of angiotensin II with an angiotensin II receptor ona cell membrane competitively or non-competitively. Compounds havingsuch an angiotensin II antagonistic activity are known to have an actionto attenuate the strong vasoconstrictive action and vascular smoothmuscle growth action induced by angiotensin II, and alleviate symptomsof hypertension.

A compound having an angiotensin II antagonistic activity used in thepreset invention may be peptidic or non-peptidic, and a compound such asa non-peptidic compound having the antagonistic activity which isadvantageous in, for example, long acting time is preferable. As acompound having the angiotensin II antagonistic activity, a compoundhaving an oxygen atom in its molecule is preferable and, inter alia, acompound such as a compound having an ether linkage or a carbonyl group(the carbonyl group may form a hydroxyl group by resonance) ispreferable, a compound such as a compound having an ether linkage or aketone derivative is more preferable and, inter alia, a compound such asan ether derivative is preferable.

As a non-peptidic compound having angiotensin II antagonistic activity,imidazole derivatives are disclosed in JP-A 56-71073, JP-A 56-71074,JP-A 57-98270, JP-A 58-157768, U.S. Pat. No. 4,355,040, U.S. Pat. No.4,340,598 etc., improved imidazole derivatives are disclosed inEP-253310, EP-291969, EP-324377, EP-403158, WO-9100277, JP-A 63-23868,JP-A 1-117876 etc., pyrrole, pyrazole and triazole derivatives aredisclosed in U.S. Pat. No. 5,183,899, EP-323841, EP-409332, JP-A1-287071 etc., benzimidazole derivative are disclosed in U.S. Pat. No.4,880,804, EP-0392317, EP-0399732, EP-0400835, EP-425921, EP-459136,JP-A 3-63264 etc., azaindene derivatives are disclosed in EP-399731etc., pyrimidone derivatives are disclosed in EP-407342 etc.,quinazoline derivatives are disclosed in EP-411766 etc., xanthinederivatives are disclosed in EP-430300 etc., fused imidazole derivativesare disclosed in EP-434038 etc., pyrimidinedione derivatives aredisclosed in EP-442473 etc., thienopyridone derivatives are disclosed inEP-443568 etc., and heterocyclic compounds are disclosed in EP-445811,EP-483683, EP-518033, EP-520423, EP-588299, EP-603712 etc.Representative compounds of the above compounds are described in Journalof Medicinal Chemistry, (Vol. 39, No. 3, pp 625-656, 1996). As anon-peptidic compound having angiotensin II antagonistic activity, inaddition to the aforementioned compounds described in the knownliterature, any compounds may be used as long as they are non-peptidiccompounds having the angiotensin II antagonistic activity, inter alia,Losartan (DuP753), Losartan potassium, Eprosartan (SK&F108566),Candesartan cilexetil (TCV-116), Valsartan (CGP-48933), Telmisartan(BIBR277), Irbesartan (SR47436), Tasosartan (ANA-756), Olmesartanmedoxomil and active metabolites thereof (Candesartan, Olmesartan etc.)are preferably used.

In addition, as a non-peptidic compound having the angiotensin IIantagonistic activity, for example, a benzimidazole derivativerepresented by the formula (I):

wherein R¹ denotes a group which can form an anion or a group which canbe converted into the group which can form an anion, X denotes that aphenylene group and a phenyl group are bound directly or via a spacerhaving no more than 2 of atom chains, n denotes an integer of 1 or 2, aring A denotes a benzene ring optionally further having a substituent,R² denotes a group which can form an anion or a group which can beconverted into the group which can form an anion, and R³ denotes ahydrocarbon residue which may be bound via a hetero atom and may have asubstituent (preferably hydrocarbon residue which may have a substituentand is bound via an oxygen atom) or a salt thereof is preferably used.

In the above formula (I), examples of a group which can form an anion (agroup having a hydrogen atom which can be liberated as a proton) as R¹include (1) a carboxyl group, (2) a tetrazolyl group, (3) atrifluoromethanesulfonic acid amide group (—NHSO₂CF₃), (4) a phosphoricacid group, (5) a sulfonic acid group, and (6) 5 to 7-membered(preferably 5 to 6-membered) monocyclic optionally substitutedheterocyclic residue containing 1 or 2 or more of N, S or O.

Examples of the “5 to 7-membered (preferably 5 to 6-membered) monocyclicoptionally substituted heterocyclic residue containing 1 or 2 or more ofN, S or O” include

etc. The bond between the heterocyclic residue represented by R¹ and thephenyl group to be bound with the heterocyclic residue includes not onlythe aforementioned carbon-carbon binding but also binding via one of aplurality of nitrogen atoms when g in the above formula denotes —NH— orthe like. For example, when R¹ is represented by

specifically, there are

respectively. Other examples of binding via a nitrogen atom include

etc.

In the above formula, g denotes —CH₂—, —NH—, —O— or—S(O)_(m)—, >=Z, >=Z″ and >=Z″ denote a carbonyl group, a thiocarbonylgroup or an optionally oxidized sulfur atom (e.g., S, S(O), S(O)₂ etc.)(preferably carbonyl or thiocarbonyl group, more preferably carbonylgroup), and m denotes an integer of 0, 1 or 2.

As a heterocyclic residue represented by R¹, for example, a group havingan —NH— group or an —OH group as a proton donor and a carbonyl group, athiocarbonyl group, a sulfinyl group or the like as a proton acceptor atthe same time, such as an oxadiazolone ring, an oxadiazolothione ring ora thiadiazolone ring is preferable. In addition, a heterocyclic residuedenoted by R¹ may form a fused ring by binding with a cyclic substituentand, as a heterocyclic residue represented by R¹, 5 or 6-membered ringresidue is preferable, and 5-membered ring residue is more preferable.

As a heterocyclic residue represented by R¹, a group represented by theformula;

wherein i denotes —O— or —S—, j denotes >═O, >═S or >═S(O)_(m), and m isas defined above (inter alia, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-thioxo-1,2,4-oxadizole-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl, among them,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) is preferable.

In addition, the heterocyclic residue (R¹) has tautomers as describedbelow. For example, when Z=O and g=O in

three tautomers of a′, b′ and c′ are present as described by:

and a heterocyclic residue represented by:

includes all of the aforementioned a′, b′ and c′.

A group which may form an anion as R¹ may be protected with a lower(C₁₋₄)alkyl group or an acyl group (e.g., lower (C₂₋₅)alkanoyl, benzoyletc.), each group optionally being substituted at a substitutableposition.

Examples of an optionally substituted lower (C₁₋₄)alkyl group include(1) a lower (C₁₋₄)alkyl group optionally substituted with 1 to 3 phenylgroups optionally having halogen atom, nitro, lower (C₁₋₄)alkyl, lower(C₁₋₄)alkoxy etc. (e.g., methyl, triphenylmethyl, p-methoxybenzyl,p-nitrobenzyl etc.), (2) a lower (C₁₋₄)alkoxy-lower (C₁₋₄)alkyl group(e.g., methoxymethyl, ethoxymethyl etc.), and (3) a group represented bythe formula —CH(R⁴)—OCOR⁵ [wherein R⁴ denotes (a) hydrogen, (b) astraight or branched lower alkyl group having a carbon number of 1 to 6(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, neopentyl etc.), (c) a straight or branched loweralkenyl group having a carbon number of 2 to 6 or (d) a cycloalkyl grouphaving a carbon number of 3 to 8 (e.g., cyclopentyl, cyclohexyl,cycloheptyl etc.) and R⁵ denotes (a) a straight or branched lower alkylgroup having a carbon number of 1 to 6 (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neopentyl etc.), (b) a straight or branched lower alkenyl group having acarbon number of 2 to 6, (c) a lower alkyl group having a carbon numberof 1 to 3 substituted with a cycloalkyl group having a carbon number of3 to 8 (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.) or anoptionally substituted aryl group (e.g., phenyl or naphthyl groupoptionally having halogen atom, nitro, lower (C₁₋₄)alkyl, lower(C₁₋₄)alkoxy etc.) (e.g., benzyl, p-chlorobenzyl, phenethyl,cyclopentylmethyl, cyclohexylmethyl etc.), (d) a lower alkenyl grouphaving a carbon number of 2 to 3 substituted with cycloalkyl having acarbon number of 3 to 8 or an optionally substituted aryl group (e.g.,phenyl or naphthyl group optionally having halogen atom, nitro, lower(C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc.) (e.g., groups having an alkenylpart such as vinyl, propenyl, allyl, isopropenyl etc. such as cinnamyletc.), (e) an optionally substituted aryl group (e.g., phenyl ornaphthyl group optionally having halogen atom, nitro, lower (C₁₋₄)alkyl,lower (C₁₋₄)alkoxy etc. such as phenyl, p-tolyl, naphthyl etc.), (f) astraight or branched lower alkoxy group having a carbon number of 1 to 6(e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy etc.), (g)a straight or branched lower alkenyloxy group having a carbon number of2 to 8 (e.g., allyloxy, isobutenyloxy etc.), (h) a cycloalkyloxy grouphaving a carbon number of 3 to 8 (e.g., cyclopentyloxy, cyclohexyloxy,cycloheptyloxy etc.), (i) a lower alkoxy group having a carbon number of1 to 3 substituted with cycloalkyl having a carbon number of 3 to 8(e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.) or an optionallysubstituted aryl group (e.g., phenyl or naphthyl group optionally havinghalogen atom, nitro, lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc.) (e.g.,groups having an alkoxy part such as methoxy, ethoxy, n-propoxy,isopropoxy etc. such as benzyloxy, phenethyloxy, cyclopentylmethoxy,cyclohexylmethoxy etc.), (j) a lower alkenyloxy group having a carbonnumber of 2 to 3 substituted with cycloalkyl having a carbon number of 3to 8 (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.) or an optionallysubstituted aryl group (e.g., phenyl or naphthyl group optionally havinghalogen atom, nitro, lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc.) (e.g.,groups having an alkenyloxy part such as vinyloxy, propenyloxy,allyloxy, isopropenyloxy etc. such as cinnamyloxy etc.) or (k) anoptionally substituted aryloxy group (e.g., phenoxy or naphthoxy groupoptionally having halogen atom, nitro, lower (C₁₋₄)alkyl, lower(C₁₋₄)alkoxy etc. such as phenoxy, p-nitrophenoxy, naphthoxy etc.)].

In addition, a group which may form an anion as R¹ may have asubstituent such as an optionally substituted lower (C₁₋₄)alkyl group(examples thereof include the same “optionally substituted lower(C₁₋₄)alkyl group” as that exemplified as a protecting group for theaforementioned group which can form an anion as R¹), halogen atom,nitro, cyano, lower (C₁₋₄)alkoxy, and amino optionally substituted with1 to 2 lower (C₁₋₄)alkyl(s), at a substitutable position, in addition toa protecting group such as the aforementioned optionally substitutedlower (C₁₋₄)alkyl group and acyl group (e.g., lower (C₂₋₅)alkanoyl,benzoyl etc.).

In the aforementioned formula, a group which can be converted into agroup which can form an anion (a group having a hydrogen atom which canbe liberated as a proton) as R¹ may be a group which can be convertedinto a group which can form an anion under the biological, that is,physiological conditions (e.g., a reaction in a living body such asoxidation, reduction or hydrolysis by an enzyme in a living body)(so-called prodrug), or may be a group which can be converted into agroup which can form an anion represented by R¹ by a chemical reaction(so-called synthetic intermediate) such as cyano, anN-hydroxycarbamimidoyl group (—C(═N—OH)—NH₂), or (1) a carboxyl group,(2) a tetrazolyl group, (3) a trifluoromethanesulfonic acid amide group(—NHSO₂CF₃), (4) a phosphoric acid group, (5) a sulfonic acid group, and(6) an optionally substituted 5 to 7-membered (preferably 5 or6-membered) monocyclic heterocyclic residue containing 1 or 2 or more ofN, S or O, each being protected with an optionally substituted lower(C₁₋₄)alkyl group or acyl group.

As R¹, carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl(preferably tetrazolyl) optionally protected with an optionallysubstituted lower (C₁₋₄)alkyl (e.g., methyl, triphenylmethyl,methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl etc.) or anacyl group (e.g., lower (C₂₋₅)alkanoyl, benzoyl etc.), or cyano, orN-hydroxycarbamimidoyl (preferably cyano) is preferable and, inter alia,cyano is preferably used.

In the above formula, X denotes that adjacent phenylene group and phenylgroup are bound directly or via no more than 2 of atom chains(preferably direct binding) and, as a spacer having no more than 2 ofatom chains, any divalent chains in which the number of atomsconstituting a straight part is 1 or 2 may be used, and the spacer mayhave a side chain. Specifically, lower (C₁₋₄)alkylene in which thenumber of atoms constituting a straight part is 1 or 2, —CO—, —O—, —S—,—NH—, —CO—NH—, —O—CH₂—, —S—CH₂—, —CH═CH— and the like can be mentioned.

In the above formula, n denotes an integer of 1 or 2 (preferably 1).

In the above formula, a ring A denotes a benzene ring optionally furtherhaving an substituent in addition to a substituent R², and examples ofthe substituent include (1) halogen (e.g., F, Cl, Br etc.), (2) cyano,(3) nitro, (4) optionally substituted lower (C₁₋₄)alkyl, (5) lower(C₁₋₄)alkoxy, (6) optionally substituted amino group (e.g., amino,N-lower (C₁₋₄) alkylamino (e.g., methylamino etc.), N,N-di-lower(C₁₋₄)alkylamino (e.g., dimethylamino etc.), N-arylamino (e.g., phenylaminoetc.), alicyclic amino (e.g., morpholino, piperidino, piperazino,N-phenylpiperazino etc.) etc.), (7) a group represented by the formula—CO-D′ [wherein D′ denotes a hydroxyl group, or lower (C₁₋₄)alkoxy inwhich the alkyl part may be substituted with hydroxyl group, lower(C₁₋₄)alkoxy, lower (C₂₋₆)alkanoyloxy (e.g., acetoxy, pivaloyloxy etc.),lower (C₁₋₆)alkoxycarbonyloxy (e.g., methoxycarbonyloxy,ethoxycarbonyloxy etc.) or lower (C₃₋₆)cycloalkoxycarbonyloxy (e.g.,cyclohexyloxycarbonyloxy etc.)], (8) tetrazolyl, atrifluoromethanesulfonic acid amide group, a phosphoric acid group and asulfonic acid group which may be protected with an optionallysubstituted lower (C₁₋₄)alkyl (examples thereof include the same“optionally substituted lower(C₁₋₄)alkyl group” as that exemplified as aprotecting group for the aforementioned group which can form an anion asR¹) or acyl (e.g., lower (C₂₋₅)alkanoyl, benzoyl etc.).

These substituents may replace 1 to 2 substitutable positions on thebenzene ring at the same time and, as a substituent which is furtherpossessed by a ring A in addition to the substituent R², an optionallysubstituted lower (C₁₋₄)alkyl (e.g., lower (C₁₋₄)alkyl optionallysubstituted with hydroxyl group, carboxyl group, halogen etc.), halogenand the like are preferable, and it is more preferable that a ring Adoes not have a substituent in addition to the substituent R².

In the above formula, examples of a group which can form an anion (agroup having a hydrogen atom which can be liberated as a proton) as R²include (1) an optionally esterified or amidated carboxyl group, (2) atetrazolyl group, (3) a trifluoromethanesulfonic acid amide group(—NHSO₂CF₃), (4) a phosphoric group, (5) a sulfonic acid group, and thelike, and these groups may be protected with an optionally substitutedlower alkyl group (examples thereof include the same “optionallysubstituted lower (C₁₋₄)alkyl group” as that exemplified as a protectinggroup for the aforementioned group which can form an anion as R¹) or anacyl group (e.g., lower (C₂₋₅)alkanoyl, benzyl etc.), and any groups maybe used as long as they are a group which can form an anion or a groupwhich can be converted into the group which can form an anion, under thebiological, that is, physiological conditions (e.g., a reaction in aliving body such as oxidation, reduction and hydrolysis by an enzyme ina living body) or chemically.

Examples of an optionally esterified or amidated carboxyl as R² includea group represented by the formula —CO-D [wherein D denotes (1) hydroxylgroup, (2) optionally substituted amino (e.g., amino, N-lower(C₁₋₄)alkylamino, N,N-di-lower (C₁₋₄) alkylamino etc.) or (3) optionallysubstituted alkoxy {e.g., (i) a lower (C₁₋₆)alkoxy group in which thealkyl part may be substituted with hydroxyl group, optionallysubstituted amino (e.g., amino, N-lower (C₁₋₄)alkylamino, N,N-di-lower(C₁₋₄) alkylamino, piperidino, morpholino etc.), halogen, lower (C₁₋₄)alkoxy, lower (C₁₋₆)alkylthio, lower (C₃₋₈)cycloalkoxy or optionallysubstituted dioxolenyl (e.g., 5-methyl-2-oxo-1,3-dioxolen-4-yl etc.), or(ii) a group represented by the formula —O—CH(R⁶)—OCOR⁷ [wherein R⁶denotes (a) hydrogen, (b) a straight or branched lower alkyl grouphaving a carbon number of 1 to 6 (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyletc.), (c) a straight or branched lower alkenyl group having a carbonnumber of 2 to 6 or (d) a cycloalkyl group having a carbon number of 3to 8 (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.) and R⁷ denotes(a) a straight or branched lower alkyl group having a carbon number of 1to 6 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl etc.), (b) a straightor branched lower alkenyl group having a carbon number of 2 to 6, (c) alower alkyl group having a carbon number of 1 to 3 substituted with acycloalkyl group having a carbon number of 3 to 8 (e.g., cyclopentyl,cyclohexyl, cycloheptyl etc.) or an optionally substituted aryl group(e.g., phenyl or naphthyl group optionally having halogen atom, nitro,lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc.) (e.g., benzyl,p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl etc.),(d) a lower alkenyl group having a carbon number of 2 to 3 substitutedwith cycloalkyl having a carbon number of 3 to 8 or optionallysubstituted aryl group (e.g, phenyl or naphthyl group optionally havinghalogen atom, nitro, lower (C₁₋₄)alkyl, (C₁₋₄) alkoxy etc.) (e.g.,groups having an alkenyl part such as vinyl, propenyl, allyl,isopropenyl etc. such as cinnamyl etc.), (e) an optionally substitutedaryl group (e.g., phenyl or naphthyl group optionally having halogenatom, nitro, lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc. such as phenyl,p-tolyl, naphthyl etc.), (f) a straight or branched lower alkoxy grouphaving a carbon number of 1 to 6 (e.g., methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy,isopentyloxy, neopentyloxy etc.), (g) a straight or branched loweralkenyloxy group having a carbon number of 2 to 8 (e.g., allyloxy,isobutenyloxy etc,), (h) a cycloalkyloxy group having a carbon number of3 to 8 (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy etc.), (i) alower alkoxy group having a carbon number of 1 to 3 substituted withcycloalkyl having a carbon number of 3 to 8 (e.g., cyclopentyl,cyclohexyl, cycloheptyl etc.) or an optionally substitute aryl group(e.g., phenyl or naphthyl group optionally having halogen atom, nitro,lower (C₁₋₄)alkyl lower, (C₁₋₄)alkoxy etc.) (e.g., groups having analkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy etc. such asbenzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy etc.) (j)a lower alkenyloxy group having a carbon number of 2 to 3 substitutedwith cycloalkyl having a carbon number of 3 to 8 (e.g., cyclopentyl,cyclohexyl, cycloheptyl etc.) or an optionally substituted aryl group(e.g., phenyl or naphthyl group optionally having halogen atom, nitro,lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc.) (e.g., groups having analkenyloxy part such as vinyloxy, propenyloxy, allyloxy, isopropenyloxyetc. such as cinnamyloxy etc.) or (k) an optionally substituted aryloxygroup (e.g., phenoxy or naphthoxy group optionally having halogen atom,nitro, lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy etc. such as phenoxy,p-nitrophenoxy, naphthoxy etc.)]}].

As R², optionally esterified carboxyl is preferable, and examplesthereof include —COOH and a salt thereof, —COOMe, —COOEt, —COOtBu,—COOPr, pivaloyloxymethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl,propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl,1-(acetoxy)ethoxycarbonyl, 1-(isobutyryloxy)ethoxycarbonyl,cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl,cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like,and any groups may be used as far as they are a group which can form ananion (e.g., COO⁻, a derivative thereof etc.) or a group which can beconverted into the group which can form an anion, under the biological,that is, physiological conditions (e.g., a reaction in a living bodysuch as oxidation, reduction and hydrolysis by an enzyme in living body)or chemically, or it may be a carboxyl group, or a prodrug thereof.

As the R², a group represented by the formula —CO-D [wherein D denotes(1) a hydroxyl group or (2) lower (C₁₋₄) alkoxy in which the alkyl partmay be substituted with hydroxyl group, amino, halogen, lower(C₂₋₆)alkanoyloxy (e.g., acetoxy, pivaloyloxy etc.), lower(C₃₋₈)cycloalkanoyloxy, lower (C₁₋₆)alkoxycarbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy etc.), lower(C₃₋₈)cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy etc.),lower (C₁₋₄)alkoxy or lower (C₃₋₈)cycloalkoxy] is preferable and, interalia, carboxyl esterified with lower(C₁₋₄)alkyl (preferably methyl orethyl) is preferable.

In the above formula, examples of the “hydrocarbon residue” in the“hydrocarbon residue which may be bound via a hetero atom and may have asubstituent” represented by R³ include (1) an alkyl group, (2) analkenyl group, (3) an alkynyl group, (4) a cycloalkyl group, (5) an arylgroup, (6) an aralkyl group and the like, and, inter alia, an alkylgroup, an alkenyl group and a cycloalkyl group are preferable.

The (1) alkyl group may be a straight or branched lower alkyl grouphaving a carbon number of around 1 to 8, and examples thereof includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, i-pentyl, hexyl, heptyl, octyl etc.

The (2) alkenyl group may be a straight or branched lower alkenyl grouphaving a carbon number of around 2 to 8, and examples thereof includevinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl and 2-octenyl.

The (3) alkynyl group may be a straight or branched lower alkynyl grouphaving a carbon number of around 2 to 8, and examples thereof includeethynyl, 2-propynyl, 2-butynyl, 2-penthynyl and 2-octynyl.

Examples of the (4) cycloalkyl group include lower cycloalkyl having acarbon number of around 3 to 6, for example, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The aforementioned alkyl group, alkenyl group, alkynyl group orcycloalkyl group may be substituted with a hydroxyl group, an optionallysubstituted amino group (e.g., amino, N-lower (C₁₋₄) alkylamino,N,N-di-lower (C₁₋₄)alkylamino etc.), halogen, lower (C₁₋₄)alkoxy group,or lower (C₁₋₄)alkylthio group.

Examples of the (5) aralkyl group include phenyl-lower (C₁₋₄)alkyl suchas benzyl and phenethyl, and examples of the (6) aryl group includephenyl.

The aforementioned aralkyl group or aryl group may have, for example,halogen (e.g., F, Cl, Br etc.), nitro, optionally substituted aminogroup (e.g., amino, N-lower (C₁₋₄)alkylamino, N,N-di-lower(C₁₋₄)alkylamino etc.), lower (C₁₋₄)alkoxy (e.g., methoxy, ethoxy etc.),lower (C₁₋₄)alkylthio (e.g., methylthio, ethylthio etc.), or lower(C₁₋₄)alkyl (e.g., methyl, ethyl etc.) at an arbitrary position on thebenzene ring.

Among the forgoing, as the “hydrocarbon residue” in the “hydrocarbonresidue which may be bound via a hetero atom and may have a substituent”represented by R³, an optionally substituted alkyl or alkenyl (e.g.,lower (C₁₋₅)alkyl or lower (C₂₋₅)alkenyl group optionally substitutedwith hydroxyl group, amino group, halogen or lower (C₁₋₄)alkoxy group)is preferable and, inter alia, lower (C₁₋₅)alkyl (more preferably ethyl)is preferable.

Examples of the “hetero atom” in the “hydrocarbon residue which may bebound via a hetero atom and may have a substituent” represented by R³include —O—, —S(O)_(m)— [m denotes an integer of 0 to 2], —NR′— [R′denotes a hydrogen atom or lower (C₁₋₄)alkyl] and the like, and, interalia, —O— is preferably used.

Among the foregoing, as R³, a lower (C₁₋₅)alkyl group and lower(C₂₋₅)alkenyl group which may be bound via —O—, —S(O)_(m)— [m denotes aninteger of 0 to 2] or —NR′—[R′ denotes hydrogen atom or lower(C₁₋₄)alkyl] and may be substituted with an substituent selected from ahydroxyl group, an amino group, a halogen and a lower (C₁₋₄)alkoxy groupare preferable, and, inter alia, lower (C₁₋₅)alkyl and lower(C₁₋₅)alkoxy (more preferable ethoxy) are preferable.

Among compounds having an angiotensin II antagonistic activityrepresented by the formula (I), a benzimidazole-7-carboxylic acidderivative represented by the formula (I′):

(wherein R¹ denotes (1) a carboxyl group, (2) a tetrazolyl group or (3)a group represented by the formula:

[wherein i denotes —O— or —S—, j denotes >═O, >═S or >═S(O)_(m), and mis as defined above], ring A denotes a benzene ring optionallysubstituted with optionally substituted lower (C₁₋₄) alkyl (e.g., lower(C₁₋₄)alkyl optionally substituted with hydroxyl group, carboxyl groupor halogen) or halogen in addition to the substituent R², preferably abenzene ring having no substituent other than the substituent R², R²denotes a group represented by the formula —CO-D [wherein D denotes (1)hydroxyl group or (2) lower (C₁₋₄)alkoxy in which the alkyl part may besubstituted with hydroxyl group, amino, halogen, lower (C₂₋₆)alkanoyloxy(e.g., acetoxy, pivaloyloxy etc.), lower (C₃₋₈) cycloalkanoyloxy, lower(C₁₋₆)alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxyetc.), lower (C₃₋₈) cycloalkoxycarbonyloxy (e.g.,cyclohexyloxycarbonyloxy etc.), lower (C₁₋₄)alkoxy or lower(C₃₋₈)cycloalkoxy], R³ denotes lower (C₁₋₅)alkyl or lower (C₂₋₅)alkenylgroup which may be bound via —O—, —S(O)_(m)— [m denotes an integer of 0to 2] or —NR′— [R′ denotes hydrogen atom or lower (C₁₋₄)alkyl] and maybe substituted with a substituent selected from a hydroxyl group, anamino group, a halogen and lower (C₁₋₄)alkoxy group (preferably lower(C₁₋₅)alkyl or lower (C₁₋₅)alkoxy; more preferably ethoxy)]), or apharmaceutically acceptable salt thereof is preferable, and, inter alia,2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid [Candesartan], 1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate[Candesartan cilexetil], pivaloyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate,and2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a salt thereof etc. are preferable.

Of the aforementioned compounds having an angiotensin II antagonisticactivity,2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid (hereinafter sometimes to be abbreviated as compound A) and a saltthereof are particularly preferable.

The aforementioned benzimidazole derivative can be synthesized by theknown method described in, for example, EP-425921, EP-459136, EP-553879,EP-578125, EP-520423 and EP-668272 or a similar method. When Candesartancilexetil is used, it is better to use the stable C-type crystaldescribed in EP-459136.

A compound having an angiotensin II antagonistic activity or a prodrugthereof used in the present invention may be itself or apharmaceutically acceptable salt thereof. When the compound having anangiotensin II antagonistic activity has an acidic group such as acarboxyl group and the like, examples of such the salt include saltswith inorganic bases (e.g., alkali metal such as sodium, potassium etc.,alkaline earth metal such as calcium, magnesium etc., transition metalsuch as zinc, iron, copper etc.) or salts with organic bases (e.g.,organic amines such as trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine and N,N′-dibenzylethylenediamine, basic amino acidssuch as arginine, lysine and ornithine).

When a compound having an angiotensin II antagonistic activity has abasic group such as an amino group and the like, examples are salts withinorganic acids or organic acids (e.g., hydrochloric acid, nitric acid,sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formicacid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid etc.) or acidic amino acids such as aspartic acidand glutamic acid.

A prodrug of a compound having an angiotensin II antagonistic activityused in the present invention [hereinafter, referred to as AIIantagonistic compound in some cases] refers to a compound which isconverted into the AII antagonistic compound by a reaction with anenzyme, stomach acid or the like under the physiological conditions in aliving body, that is, a compound which undergoes enzymatic oxidation,reduction, hydrolysis or the like, and is changed into the AIIantagonistic compound, or a compound which undergoes hydrolysis bystomach acid or the like, and is changed into the AII antagonisticcompound. Examples of a prodrug of the AII antagonistic compound includea compound in which an amino group of the AII antagonistic compound isacylated, alkylated or phosphorylated (e.g., a compound in which anamino group of the AII antagonistic compound is eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated ortert-butylated); a compound in which a hydroxyl group of the AIIantagonistic compound is acylated, alkylated, phosphorylated or borated(e.g., a compound in which a hydroxyl group of the AII antagonisticcompound is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated); a compound in which a carboxyl groupof the AII antagonistic compound is esterified or amidated (e.g., acompound in which a carboxyl group of the AII antagonistic compound isethylesterified, phenylesterified, carboxymethylesterified,dimethylaminomethylesterified, pivaloyloxymethylesterified,ethoxycarbonyloxyethylesterified, phthalidylesterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified,cyclohexyloxycarbonyloxyethylesterified, or methylamidated); and thelike. These compounds can be prepared from the AII antagonistic compoundby the known method per se. Alternatively, a prodrug of the AIIantagonistic compound may be a prodrug which is changed into the AIIantagonistic compound under the physiological conditions described in“Development of Medicaments”, vol. 7, Molecular Design, pp 163-198published by Hirokawashoten in 1990.

The AII antagonistic compound may be either a hydrate or a non-hydrate.

The PPARγ agonist-like substance used in the present invention onlyneeds to be an agonist against PPARγ, and may be any substance as longas it expresses the activity.

The PPARγ agonist-like substance is preferably, for example, a substanceshowing a clear PPARγ agonist-like activity in vitro at a concentrationof not more than 10 μM and the like.

As preferable examples of the PPARγ agonist-like substance, insulinsensitizers such as troglitazone, rosiglitazone, englitazone,ciglitazone, pioglitazone, PGJ₂, GI-262570, JTT-501, MCC-555, YM-440,KRP-297, CS-011, FK-614 and the like can be mentioned.

In the present invention, the compound having an angiotensin IIantagonistic activity and a PPARγ agonist-like substance is not limitedto the above-mentioned examples and any substance can be used as long asit has such activity. In addition, the substance may further have aPPARα functional regulatory activity (agonistic or antagonisticactivity).

The agent of the present invention may contain a compound having anangiotensin II antagonistic activity in combination with a PPARγagonist-like substance, and as preferable combinations, for example, acombination of the aforementioned insulin sensitizer having a PPARγagonistic activity (e.g., troglitazone, rosiglitazone, englitazone,ciglitazone, pioglitazone and the like) and compound A and the like canbe mentioned.

As the insulin sensitizer having a PPARγ agonistic activity, forexample, troglitazone has been reported to show a body weight gainingaction in patients with type II diabetes (Diabetes, 47, suppl. 1, A18,No. 69, 1998). The body weight gain in patients with diabetes inducesedema and swelling, and aggravation of symptoms may cause a gravecirculatory diseases such as cardiac hypertrophy and the like, causing aserious problem in the treatment of diabetes.

Therefore, the use of a compound per se, which has an angiotensin IIantagonistic activity and an insulin resistance-improving activity incombination, such as compound A, can avoid use of an insulin sensitizercausing body weight gain, or can markedly decrease the dose of aninsulin sensitizer itself. As compared to the single use of an insulinsensitizer, a combined use with an insulin sensitizer strikinglysuppresses an expression of body weight gain or a possibility thereof,which in turn highly advantageously avoids aggravation of diabeticsymptoms.

The dose of the agent of the present invention only needs to fall withinthe range of an effective amount of each substance.

For example, while the dose of a compound having an angiotensin IIantagonistic activity varies depending on the subject of administration,administration route, target disease, symptom and the like, in the caseof oral administration to an adult patient with diabetes (body weight 60kg), a dose is generally about 0.001 to about 500 mg, preferably about0.1 to about 100 mg, more preferably about 2.5 to about 60 mg, which isadministered in 1 to 3 portions a day.

The dose of a PPARγ agonist-like substance to patients with diabetes isabout 0.1 to about 600 mg/day, preferably about 0.5 to about 240 mg/day,more preferably about 1.0 to about 100 mg/day. These amounts may beadministered once a day or in 2 or 3 portions a day.

The administration ratio of a compound having an angiotensin IIantagonistic activity and a PPARγ agonist-like substance (PPARγagonist-like substance/compound having an angiotensin II antagonisticactivity) is about 0.002 to about 60000, preferably about 0.005 to about2400, more preferably about 0.02 to about 40, more preferably about 0.4to about 8.

The body weight gain inhibitor of the present invention (hereinaftersometimes to be simply abbreviated as an “agent of the presentinvention”) shows low toxicity, and can be used as it is or as apharmaceutical composition by mixing with a pharmacologically acceptablecarrier by a method known per se, as a prophylactic/therapeutic agentfor after-mentioned various diseases in mammals (e.g., human, mouse,rat, rabbit, dog, cat, bovine, horse, swine, monkey and the like).

Herein, as a pharmaceutically acceptable carrier, various organic orinorganic carrier materials which are conventional as a pharmaceuticalmaterial are used, and is incorporated as an excipient, a lubricant, abinder or a disintegrating agent in a solid preparation; as a solvent, asolubilizer, a suspending agent, an isotonic, a buffer or a soothingagent in a liquid preparation. If necessary, pharmaceutical additivessuch as a preservative, an antioxidant, a colorant and a sweetener maybe used.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, dextrin, pullulan, light silicicanhydride, synthetic aluminum silicate and magnesium aluminatemetasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinized starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrating agent include lactose,sucrose, starch, carboxymethylcellulose, calciumcarboxylmethylcellulose, sodium crosscarmerose, sodiumcarboxymethylstarch, light silicic anhydride and low-substitutedhydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological saline, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizer include polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride and monostearicacid glycerin; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose; polysorbates and polyoxyethylene hydrogenatedcastor oil.

Preferable examples of the isotonic include sodium chloride, glycerin,D-mannitol, D-sorbitol and glucose.

Preferable examples of a buffer include buffers such as phosphate,acetate, carbonate and citrate.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include paraoxy benzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid and sorbic acid.

Preferable examples of the antioxidant include sulfite and ascorbate.

Preferable examples of the colorant include water-soluble edible tarpigments (e.g., edible pigments such as edible red Nos. 2 and 3, edibleyellow Nos. 4 and 5, edible blue Nos. 1 and 2), water-insoluble lakepigments (e.g., aluminum salt of the aforementioned water-soluble tarpigments), and natural pigments (e.g., β-carotene, chlorophyll andcolcothar).

Preferable examples of the sweetener include sodium saccharine,dipotassium glycyrrhizinate, aspartame and stevia.

The dosage form of the pharmaceutical composition includes oralpreparations such as tablets, capsules (including soft capsules andmicrocapsules), granules, powders, syrups, emulsions, suspensions andsustained-releasing preparations; and parenteral preparations such asinjections (e.g., subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection, intravitreousinjection), eye drops, external preparations (e.g., transnasalpreparation, transdermal preparation and ointment), suppositories (e.g.,rectal suppository and vaginal suppository), pellets and drops, andthese can be safely administered either orally or parenterally.

The pharmaceutical compositions can be prepared by conventional methodsin the technical field of pharmacy, such as the methods described in theJapanese Pharmacopoeia. Specific process for producing preparations willbe described in detail below.

For example, oral preparations are produced by adding, for example, anexcipient (e.g., lactose, sucrose, starch, D-mannitol etc.), adisintegrating agent (e.g., calcium carboxymethylcellulose etc.), abinder (e.g., gelatinized starch, gum arabic, carboxymethylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone etc.) or a lubricant (e.g.,talc, magnesium stearate, polyethylene glycol 6000 etc.) to an activeingredient, compression-molding them and, if necessary, coating themolded material with a coating base by a method known per se for thepurpose of taste masking, enteric coating or sustainability.

Examples of the coating base include a sugar-coated base, awater-soluble film coating base, an enteric film coating base, asustained-releasing film coating base and the like.

As the sugar-coated base, sucrose is used, and one or two or moremembers selected from talc, precipitated calcium carbonate, gelatin, gumarabic, pullulan, carnauba wax and the like may be used jointly.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and methylhydroxyethylcellulose; syntheticpolymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name), Rohmpharma] andpolyvinylpyrrolidone; polysaccharides such as pullulan.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, and cellulose acetate phthalate; acrylicacid polymers such as methacrylic acid copolymer L [Eudragit L (tradename), Rohmpharma], methacrylic acid copolymer LD [Eudragit L-30D55(trade mane), Rohmpharma], and methacrylic acid copolymer S [Eudragit S(trade name), Rohmpharma]; and natural materials such as shellac.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose; acrylic acid polymers such asaminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)Rohmpharma], and ethyl acrylate/methyl methacrylate copolymer suspension[Eudragit NE (trade name), Rohmpharma].

The aforementioned coating bases may be used by mixing two or more kindsof them at an appropriately ratio. In addition, upon coating, a lightshielding agent such as titanium oxide and iron sesquioxide may be used.

Injections are prepared by dissolving, suspending or emulsifying anactive ingredient together with a dispersing agent (e.g., polysorbate80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol,carboxymethylcellulose, sodium arginate etc.), a preservative (e.g.,methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenoletc.), an isotonic (e.g., sodium chloride, glycerin, D-mannitol,D-sorbitol, glucose etc.) in an aqueous solvent (e.g., distilled water,physiological saline, Ringer's solution etc.) or an oily solvent (e.g.,vegetable oil such as olive oil, sesame oil, cottonseed, corn oil etc.propylene glycol). Upon this, additives such as a solubilizer (e.g.,sodium salicylate, sodium acetate etc.), a stabilizer (e.g., humanalbumin etc.) and a soothing agent (benzyl alcohol etc.) may be used.

The content of a compound having an angiotensin II antagonistic activityin a pharmaceutical composition is generally about 0.01 to about 99.9%by weight, preferably about 0.1 to about 50% by weight, of the wholepreparation.

As mentioned above, since a compound having an angiotensin IIantagonistic activity represented by compound A shows a body weight gainsuppressing action, it can be used as a body weight gain inhibitor for amammal. The mammal to be the applicable target only needs to an animalwishing to avoid body weight gain and may be an animal geneticallyhaving a risk of body weight gain or an animal suffering from alife-style related disease such as diabetes, hypertension and/orhyperlipidemia and the like. The body weight gain may be caused byexcessive food ingestion or dietary habit without nutritional balance,or induced by a prophylactic/therapeutic agent for the aforementionedlife-style related diseases. In addition, the body weight gain may bethat before reaching obesity, or that of a patient with obesity. As usedherein, the obesity is defined by a BMI (Body Mass Index: body weight(kg)÷[body height (m)]²) of not less than 25 (based on the criteria ofJAPAN SOCIETY FOR THE STUDY OF OBESITY) for Japanese, and a BMI of notless than 30 (based on WHO criteria) for Westeners.

While the agent of the present invention is preferably used as a bodyweight gain inhibitor for obese patients with diabetes, it can be alsoused for the purpose of suppressing a body weight gain of obese patientssuffering from various complications such as insulin resistance,impaired glucose tolerance; diabetes such as insulin non-dependentdiabetes, type II diabetes, type II diabetes associated with insulinresistance, type II diabetes associated with impaired glucose toleranceetc.; various complications such as hyperinsulinemia, hypertensionassociated with insulin resistance, hypertension associated withimpaired glucose tolerance, hypertension associated with diabetes (e.g.,type II diabetes etc.), hypertension associated with hyperinsulinemia,insulin resistance occurring in association with hypertension, impairedglucose tolerance occurring in association with hypertension, diabetesoccurring in association with hypertension, hyperinsulinemia occurringin association with hypertension, diabetic complications [e.g.,microangiopathy, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, diabetic cataract, large vessel disease, osteopenia,diabetic hyperosmolar coma, infectious diseases (e.g., respiratoryinfectious disease, urinary tract infectious disease, digestiveinfectious disease, infectious disease of dermal soft tissue, infectiousdisease of inferior limb etc.), diabetic gangrene, dry mouth, loweredsense of hearing, diabetic cerebrovascular disorder, diabetic peripherichematogenous disorder, diabetic hypertension and the like], diabeticcachexia, diabetic nephropathy and the like.

As applicable diseases for the compound having an angiotensin IIantagonistic activity as a physiologically active compound, diseasesdeveloped or whose onset is promoted by contraction and growth of bloodvessels or organ disorders that express via angiotensin II receptor, bythe presence of angiotensin II, or by the factors induced by thepresence of angiotensin II and the like can be mentioned.

As such diseases, for example, hypertension, blood pressure circadianrhythm abnormality, heart diseases (e.g., cardiac hypertrophy, acuteheart failure and chronic heart failure including congestive heartfailure, cardiac myopathy, angina pectoris, myocarditis, arrhythmia,tachycardia, cardiac infraction etc.), cerebrovascular disorders (e.g.,asymptomatic cerebrovascular disorder, transient ischemic attack,cerebral stroke, cerebrovascular dementia, hypertensive encephalopathy,cerebral infarction etc.), cerebral edema, cerebral circulatorydisorder, recurrence and sequela of cerebrovascular disorders (e.g.,neurotic symptom, psychic symptom, subjective symptom, disorder in dailyliving activities etc.), ischemic peripheral circulation disorder,myocardial ischemia, venous insufficiency, progression of cardiacinsufficiency after cardiac infarction, renal diseases (e.g., nephritis,glomerulonephritis, glomerulosclerosis, renal failure, thromboticmicrovasculopathy, complication of dialysis, organ dysfunction includingnephropathy by radiation damage etc.), arteriosclerosis includingatherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebralarteriosclerosis, peripheral arteriosclerosis etc.), vascularhypertrophy, vascular hypertrophy or obliteration and organ disordersafter intervention (e.g., percutaneous transluminal coronaryangioplasty, stenting, coronary angioscopy, intravascular ultrasound,intracoronary thrombolytic therapy etc.), vascular re-obliteration andrestenosis after bypass, polycythemia, hypertension, organ disorder andvascular hypertrophy after transplantation, rejection aftertransplantation, ocular diseases (e.g., glaucoma, ocular hypertensionetc.), thrombosis, multiple organ disorder, endothelial dysfunction,hypertensive tinnitus, other cardiovascular diseases (e.g., deep veinthrombosis, obstructive peripheral circulatory disorder,arteriosclerosis obliterans, obstructive thromboangiitis, ischemiccerebral circulatory disorder, Raynaud's disease, Berger disease etc.),metabolic and/or nutritional disorders (e.g., obesity, hyperlipidemia,hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremiaetc.), nerve degeneration diseases (e.g., Alzheimer's disease,Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS encephalopathyetc.), central nervous system disorders (e.g., cerebral hemorrhage,cerebral infarction, their sequela and complication, head injury, spinalinjury, cerebral edema, sensory malfunction, sensory functionaldisorder, autonomic nervous system disorder, autonomic nervous systemmalfunction, multiple sclerosis etc.), dementia, defects of memory,disorder of consciousness, amnesia, anxiety symptom, catatonic symptom,discomfort mental state, psychopathies (e.g., depression, epilepsy,alcoholism etc.), inflammatory diseases (e.g., arthritis such asrheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitisetc.; inflammation after operation and injury; remission of swelling;pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatoryintestinal diseases such as Crohn's disease, ulcerative colitis etc.;meningitis; inflammatory ocular disease; inflammatory pulmonary diseasesuch as pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonarytuberculosis etc.), allergic diseases (e.g., allergic rhinitis,conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis etc.),chronic obstructive pulmonary disease, interstitial pneumonia,pneumocytis carinni pneumonia, collagen diseases (e.g., systemic lupuserythematodes, scleroderma, polyarteritis etc.), hepatic diseases (e.g.,hepatitis including chronic hepatitis, hepatic cirrhosis etc.), portalhypertension, digestive system disorders (e.g., gastritis, gastriculcer, gastric cancer, gastric disorder after operation, dyspepsia,esophageal ulcer, pancreatitis, colon polyp, cholelithiasis,hemorrhoidal disease, varices ruptures of esophagus and stomach etc.),blood and/or myelopoietic diseases (e.g., erythrocytosis, vascularpurpura, autoimmune hemolytic anemia, disseminated intravascularcoagulation syndrome, multiple myelopathy etc.), bone diseases (e.g.,fracture, refracture, osteoporosis, osteomalacia, bone Paget's disease,sclerosing myelitis, rheumatoid arthritis, osteoarthritis of the kneeand joint tissue dysfunction owing to similar diseases and disorderetc.), solid tumor, tumors (e.g., malignant melanoma, malignantlymphoma, cancer of digestive organs (e.g., stomach, intestine etc.)etc.), cancer and cachexia following cancer, metastasis cancer,endocrinopathy (e.g., Addison's disease, Cushing's syndrome,pheochromocytoma, primary aldosteronism etc.), Creutzfeldt-Jakobdisease, urinary organ and/or male genital diseases (e.g., cystitis,prostatic hypertrophy, prostatic cancer, sex infectious disease etc.),female disorders (e.g., climacteric disorder, gestosis, endometriosis,hysteromyoma, ovarian disease, breast disease, sex infectious diseaseetc.), disease relating to environment and occupational factors (e.g.,radiation hazard, hazard by ultraviolet, infrared, or laser beam,altitude sickness etc.), respiratory diseases (e.g., cold syndrome,pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis andpulmonary embolism etc.), infectious diseases (e.g., viral infectiousdiseases with cytomegalovirus, influenza virus, herpes virus etc.,rickettsiosis, bacterial infectious disease etc.), toxemias (e.g.,sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shocksyndrome etc.), otorhinolaryngological diseases (e.g., Meniere'ssyndrome, tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.),skin diseases (e.g., keloid, hemangioma, psoriasis etc.), intradialytichypotension, myasthenia gravis, systemic diseases such as chronicfatigue syndrome and the like can be mentioned.

In addition, long-term suppression of action of angiotensin II resultsin the improvement or suppression of promotion of disorder orabnormality in the biofunction and physiological action, that causesadult disorders and various diseases linked with aging and the like,which in turn leads to the primary and secondary prophylaxis of diseasesor clinical conditions caused thereby or suppression of the progressionthereof. As the disorder or abnormality in the biofunction andphysiological action, for example, disorder or abnormality in automaticcontrolling capability of cerebral circulation and/or renal circulation,disorder of circulation (e.g., peripheral, cerebral, microcirculationetc.), disorder of blood-brain-barrier, salt susceptibility, abnormalstate of coagulation and fibrinolysis system, abnormal state of bloodand blood cell components (e.g., accentuation of platelet aggregationaction, malfunction of erythrocyte deformability, accentuation ofleukocyte adhesiveness, rise of blood viscosity etc.), production andfunction accentuation of growth factor and cytokines (e.g., PDGF, VEGF,FGF, interleukin, TNF-α, MCP-1 etc.), accentuation of production andinfiltration of inflammatory cells, accentuation of production of freeradical, liposteatosis accentuation, endothelial function disorder,endothelium, cell and organ dysfunction, edema, cell morphogenesischange of smooth muscle etc. (morphogenesis to proliferation type etc.),production and function accentuation of vasoactive substance andthrombosis inducers (endothelin, thromboxane A₂ etc.), abnormalconstriction of blood vessel etc., metabolic disorder (serum lipidabnormalities, dysglycemia etc.), abnormal growth of cell etc.,angiogenesis (including abnormal vasculogenesis during abnormalcapillary reticular formation in adventitial coat of arterioscleroticlesion) and the like can be mentioned. Of these, the present inventioncan be used as an agent for the primary and secondary prophylaxis ortreatment of organ disorders associated with various diseases (e.g.,cerebrovascular disorder and organ disorder associated therewith, organdisorder associated with circulatory disease, organ disorder associatedwith diabetes, organ disorder after intervention etc.) can be mentioned.Therefore, the agent of the present invention can be advantageously usedfor patients who should suppress body weight gain, and who haveconcurrently developed the above-mentioned diseases.

When a compound having an angiotensin II antagonistic activity is usedin combination with a PPARγ agonist-like substance in the presentinvention, these may be administered as independent preparations or maybe administered as a single combined preparation. When used in acombination of independent preparations, the timing of administration ofeach preparation is not limited, and these may be simultaneouslyadministered to a subject of administration, or may be administered in astaggered manner. The dosage forms of respective preparations may bedifferent, and the dosage form may be determined for each activeingredient, which is employed for conventional pharmaceutical agents.

When a PPARγ agonist-like substance to be used concurrently is made intoa preparation independent from the compound having an angiotensin IIantagonistic activity, the agent containing the PPARγ agonist-likesubstance may contain pharmacologically acceptable carriers. As suchcarriers, various organic or inorganic carrier substances conventionallyused as materials for preparations can be used, and added as excipient,lubricant, binder and disintegrant for solid preparations; solvent,dissolution aids, suspending agent, isotonizing agent, buffer andsoothing agent for liquid preparations; and the like. Where necessary,additives for preparation, such as preservative, antioxidant, coloringagent, sweetening agent and the like, can be also used.

As the carrier or additive, those similar to the aforementioned can bementioned.

The content of a PPARγ agonist-like substance in a pharmaceuticalcomposition containing the PPARγ agonist-like substance is generallyabout 0.01 to about 99.9% by weight, preferably about 0.1 to about 50%by weight, of the whole preparation.

The agent of the present invention is effective for the suppression ofbody weight gain observed in patient with various diseases (e.g.,diabetes and the like) and under medication of a PPARγ agonist-likesubstance (e.g., insulin sensitizer) and useful for thetreatment/prophylaxis and the like of the angiotensin II-relateddiseases (e.g., the above-mentioned hypertension and the like).

The agent of the present invention can suppress a body weight gaininduced by a PPARγ agonist-like substance, which is observed in patients(e.g., patients with diabetes) under medication of a PPARγ agonist-likesubstance to, for example, not more than about 80%.

The applicable diseases of the PPARγ agonist-like substance include, forexample, diabetes (e.g., type I diabetes, type II diabetes, gestationaldiabetes mellitus and the like), hyperlipidemia (e.g.,hypetriglyceridemia, hypercholesterolemia, hypo-high densitylipoproteinemia, postprandial hyperlipidemia and the like), diabeticcomplications (e.g., neuropathy, nephropathy, retinopathy, cataract,macroangiopathy, osteopenia and the like), impaired glucose tolerance(IGT), obesity, osteoporosis, cachexia (e.g., carcinomatous cachexia,tuberculous cachexia, diabetic cachexia, cachexia due to hemopathy,cachexia due to endocrinopathy, cachexia due to infection, or cachexiadue to acquired immune deficiency syndrome), fatty liver, hypertension,polycystic ovary syndrome, gestational diabetes mellitus, renal diseases(e.g., diabetic nephropathy, glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis, end stage renaldisease and the like), muscular dystrophy, myocardial infarction, anginapectoris, cerebrovascular disorders (e.g., cerebral infarction, stroke),insulin resistance syndrome, Syndrome X, hyperinsulinemia, sensorydisturbance in hyperinsulinemia, tumors (e.g., leukemia, breast cancer,prostatic cancer, skin carcinoma and the like), irritable bowelsyndrome, acute or chronic diarrhea, visceral obesity syndrome and thelike. In addition, the PPARγ agonist-like substance can be used for thetreatments aiming at improved insulin resistance, enhanced insulinsensitivity, and suppression of the shift from impaired glucosetolerance to diabetes. Furthermore, the agent of the present inventioncan be used for controlling appetite and food ingestion in the patientsundergoing treatments of diabetes.

For diagnostic criteria of diabetes, Japan Diabetes Society reported newdiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, and a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes and differentfrom “a condition showing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of less than 110 mg/dl or a 75 goral glucose tolerance test (75 g OGTT) 2 h level (glucose concentrationof intravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, regarding diagnostic criteria for diabetes, new diagnosticcriteria were reported by ADA (The American Diabetes Association) in1997 and by WHO in 1998.

According to these reports, diabetes is a condition where the fastingblood glucose level (glucose concentration in venous plasma) is not lessthan 126 mg/dl, and the 2-hour value (glucose concentration in venousplasma) of the 75 g oral glucose tolerance test is not less than 200mg/dl.

In addition, according to the above reports, impaired glucose toleranceis a condition where the fasting blood glucose level (glucoseconcentration in venous plasma) is less than 126 mg/dl, and the 2-hourvalue (glucose concentration in venous plasma) of the 75 g oral glucosetolerance test is not less than 140 mg/dl and less than 200 mg/dl.Furthermore, according to the ADA report, a condition where the fastingblood glucose level (glucose concentration in venous plasma) is not lessthan 110 mg/dl and less than 126 mg/dl, is called IFG (Impaired FastingGlucose). On the other hand, according to the WHO report, of theconditions of IFG (impaired fasting glucose), a condition where the2-hour value (glucose concentration in venous plasma) of the 75 g oralglucose tolerance test is less than 140 mg/dl, is called IFG (impairedFasting Glycemia).

PPARγ agonist-like substance can be used as an agent for the prophylaxisor treatment of diabetes, borderline type, impaired glucose tolerance,IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) asdefined by the above-mentioned new diagnostic criteria. Moreover, theagent of the present invention can prevent the progression of theborderline type, impaired glucose tolerance, IFG (Impaired FastingGlucose) or IFG (Impaired Fasting Glycemia) to diabetes.

In addition, the agent of the present invention can be used incombination with pharmaceutical agents such as a therapeutic agent fordiabetes, a therapeutic agent for diabetic complications, ananti-hyperlipidemia agent, an anti-hypertensive agent, a diuretic, achemotherapeutic agent, an immunotherapeutic agent and the like(hereinafter to be abbreviated as a combination drug). In addition, theagent per se of the present invention may contain such combinationdrugs. Unless otherwise specified, when simply expressed by “incombination with” in the present specification, they may be administeredas independent drugs or may be administered as a single combined drug.When used in a combination of independent drugs, the timing ofadministration of the agent of the present invention and a combinationdrug is not limited, and these may be simultaneously administered to asubject of administration, or may be administered in a staggered manner.Furthermore, two or more kinds of combination drugs may be used incombination at an appropriate ratio.

The dose of the combination drug can be suitably determined based on thedose clinically employed for each agent. In addition, the mixing ratioof the agent of the present invention and a combination drug can bedetermined depending on the subject to be administered, administrationroute, subject disease, the symptom, combination and the like.

As the therapeutic agent for diabetes include insulin preparations(e.g., animal insulin preparations extracted from the bovine or swinepancreas; human insulin preparations synthesized by a geneticengineering technique using E. coli or a yeast), α-glucosidaseinhibitors (e.g., voglibose, acarbose, miglitol, emiglitate etc.),biguanide agents (e.g., phenformin, metformin, buformin etc.), insulinsecretagogues [e.g., sulfonylurea agents (e.g., tolbutamide,glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide,glyclopyramide, glimepiride, glipizide, glybuzole etc.), repaglinide,senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1etc.], amylin agonists (e.g., pramlintide etc.), phosphotyrosinephosphatase inhibitors (e.g., vanadic acid etc.) and the like can bementioned.

As the therapeutic agents for diabetic complications, aldose reductaseinhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat,minalrestat, fidarestat, SNK-860, CT-112 etc.), neurotrophic factors(e.g., NGF, NT-3, BDNF etc.), neurotrophic factor production-promotingagents, PKC inhibitors (e.g., LY-333531 etc.), AGE inhibitors (e.g.,ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide(ALT766), EXO-226 etc.), active oxygen scavengers (e.g., thioctic acidetc.) and cerebral vasodilators (e.g., tiapride, mexiletine etc.) can bementioned.

As the anti-hyperlipidemia agents, statin compounds which arecholesterol synthesis inhibitors (e.g., pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin orsalts thereof (e.g., sodium salt) etc.), squalene synthetase inhibitorsor fibrate compounds having a triglyceride lowering effect (e.g.,bezafibrate, clofibrate, simfibrate, clinofibrate etc.) and the like canbe mentioned.

As the antihypertensive agents, angiotensin converting enzyme inhibitors(e.g., captopril, enalapril, delapril etc.), angiotensin II antagonists(e.g., losartan, candesartan cilexetil, eprosartan, valsartan,termisartan, irbesartan, tasosartan, olmesartan etc.), calciumantagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine,nicardipine etc.) and the like can be mentioned.

As the anti-obesity agents, for example, central acting anti-obesityagent (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine,amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorexetc.), pancreatic lipase inhibitors (e.g., orlistat etc.), β3 agonists(e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085,AZ40140 etc.), anorectic peptides (e.g., leptin, CNTF (ciliaryneurotropic factor) etc.), cholecystokinin agonists (e.g., lintitript,FPL-15849 etc.) and the like can be mentioned.

As the diuretics, for example, xanthine derivatives (e.g., theobrominesodium salicylate, theobromine calcium salicylate etc.), thiazidepreparations (e.g., ethiazide, cyclopenthiazide, trichlormethiazide,hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide,penfluthiazide, polythiazide, methyclothiazide etc.), anti-aldosteronepreparations (e.g., spironolactone, triamterene etc.), carbonicanhydrase inhibitors (e.g., acetazolamide etc.),chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside,indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide,bumetanide, furosemide and the like can be mentioned.

As the chemotherapeutic agents, for example, alkylation agents (e.g.,cyclophosphamide, ifosphamide etc.), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil etc.), anticancer antibiotics (e.g.,mitomycin, adriamycin etc.), plant-derived anticancer agents (e.g.,vincristine, vindesine, taxol etc.), cisplatin, carboplatin, etoposideand the like can be mentioned. Of these, furtulon, neofurtulon and thelike which are 5-fluorouracil derivatives are preferable.

As the immunotherapeutic agents, for example, icroorganism or bacterialcomponents (e.g., muramyl dipeptide derivative, picibanil etc.),polysaccharides having immunostimulant action (e.g., lenthinan,schizophyllan, krestin etc.), cytokines obtained by genetic engineeringtechniques (e.g., interferon, interleukin (IL) etc.), colony stimulatingfactor (e.g., granulocyte-colony stimulating factor, erythropoietinetc.) and the like can be mentioned, with preference given to IL-1,IL-2, IL-12 and the like.

Moreover, pharmaceutical agents having a cachexia improving actionacknowledged in animal models and clinical situations, which includecyclooxygenase inhibitors (e.g., indomethacin etc.)[Cancer Research,Vol. 49, pp. 5935-5939, 1989], progesterone derivatives (e.g., megestrolacetate) [Journal of Clinical Oncology, Vol. 12, pp. 213-225, 1994],glucosteroid (e.g., dexamethasone etc.), metoclopramide pharmaceuticalagents, tetrahydrocannabinol pharmaceutical agent (publications are thesame as the above), fat metabolism improving agents (e.g.,eicosapentanoic acid etc.)[British Journal of Cancer, Vol. 68, pp.314-318, 1993], growth hormone, IGF-1, and antibody against TNF-α, LIF,IL-6 or oncostatin M, which is a factor inducing cachexia, and the like,can be also used in combination with the pharmaceutical agent of thepresent invention.

The combination drug preferably includes:

-   1) an insulin preparation;-   2) a biguanide agent;-   3) an insulin secretagogue (such as sulfonylurea agent);-   4) a biguanide agent;-   5) an α-glucosidase inhibitor;-   6) an insulin preparation and a biguanide agent;-   7) an insulin preparation and α-glucosidase inhibitor;-   8) an insulin secretagogue (such as sulfonylurea agent) and a    biguanide agent;-   9) an insulin secretagogue (such as sulfonylurea agent) and an    α-glucosidase inhibitor;-   10) a biguanide agent and an α-glucosidase inhibitor;-   11) an insulin sensitizer (e.g., PPARγ agonist-like substance);-   12) a combination of an insulin sensitizer and the agent of the    above-mentioned 1) to 10);-   13) reducer of blood sugar and other therapeutic agent for diabetic    complication;-   14) other agents mentioned above and a combination of two or more    kinds thereof;

When the agent of the present invention is used in combination with acombination drug, the amounts of these agents can be decreased in a saferange in consideration of opposition effect of these agents.Particularly, the dose of insulin secretagogues such as insulinpreparation, sulfonylurea agent and the like, and biguanide agents canbe decreased from conventional dose. Therefore, the side effects thatwill be caused by these agents can be safely prevented. In addition, thedoses of the agents for diabetic complications, antilipidemic agents andanti-hypertensive agents can be decreased. As a result, the side effectsthat will be caused by these agents can be effectively prevented.

The present invention is explained in more detail in the following byreferring to Experimental Examples and Examples, which are not to beconstrued as limitative.

In the prescription shown as Examples, the components (additives) otherthan the active ingredient can be those listed in the JapanesePharmacopoeia, Japanese Pharmaceutical Codex or Japanese PharmaceuticalExcipients and the like.

EXPERIMENTAL EXAMPLE 1

Effect of2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid (Compound A) on Body Weight Gain of Obese Mouse

-   1) Test Method

As the obese mouse, male KKA^(y) mice (10 week old) were used. The micewere grouped by measuring the body weight, and feeding of a CE-2powdered feed (control)(n=7) and a 0.005% compound A-mixed feed (n=7)was started. At 4 days from feeding, the body weight was measured andthe amount of the body weight gain was calculated. As the normalcontrol, C57BL mice were used, and after feeding a CE-2 powdered feedfor 4 days, whether the male KKA^(y) mice of the same age became obesewas also examined.

The results are shown in mean±standard error. For the analysis ofsignificance, Student's t-test was used.

-   2) Results

The body weights of 10-week-old KKA^(y) mice and C57BL mice were41.4±0.7 g and 22.9±0.8 g, respectively, and the body weight of KKA^(y)mice was found to be significantly (p<0.01) greater. Thus, the KKA^(y)mice of this week of age were found to be in the state of obesity. Thebody weight gain of the KKA^(y) mice during the test period was 1.2±0.2g and 0.1±0.4 g, respectively, for the control group and the compoundA-mixed feed group (about 6.5 mg/kg/day), and the body weight gain wassignificantly suppressed in the compound A-mixed feed group (p<0.05).

EXPERIMENTAL EXAMPLE 2

Effect of Compound a on Body Weight Gain Induced by PPARγ Agonist-LikeSubstance (Pioglitazone)

-   1) Test Method

As the obesity rats, male Wistar fatty rats (16 week old) were used. Thebody weights were measured and the rats were grouped, after which asuspension of a drug in 0.5% methylcellulose solution was repeatedly andforcibly administered orally once a day for 7 consecutive days. After 24hr from the final administration, the body weight was measured and thebody weight gain was calculated. The results are shown in mean istandard error. For the analysis of significance, Student's t-test wasused.

-   2) Results

The amount of body weight gain of the control group was 24.4±2.4 g,whereas that of the PPARγ agonist-like substance administration group(pioglitazone hydrochloride: 0.5 mg/kg/day, p.o.) was 30.8±1.8 g,showing the propensity toward increase (p<0.05). The amount of bodyweight gain of the rats administered with a PPARγ agonist-like substance(0.5 mg/kg/day, p.o.) and compound A (1 mg/kg/day, p.o.) was 19.3±2.5 g,showing significant decrease (p<0.05) as compared to the PPARγagonist-like substance single administration group.

EXAMPLE 1 Capsule

(1) compound A 5 mg (2) Lactose 115 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 capsule 200 mg (1), (2), (3) and ½ of(4) are admixed and granulated. Thereto is added the remaining (4), andthe total amount is sealed in a gelatin capsule.

EXAMPLE 2 Tablet

(1) compound A 10 mg (2) Lactose 55 mg (3) Cornstarch 150 mg (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet250 mg (1), (2), (3), ⅔ of (4) and ½ of (5) are admixed and granulated.Thereto are added the remaining (4) and (5), and the mixture iscompression formed to give tablets.

EXAMPLE 3 Capsule

(1) compound A 5 mg (2) Pioglitazone hydrochloride 30 mg (3) Lactose 85mg (4) Microcrystalline cellulose 70 mg (5) Magnesium stearate 10 mg 1capsule 200 mg (1), (2), (3), (4) and ½ of (5) are admixed andgranulated. Thereto is added the remaining (5), and the total amount issealed in a gelatin capsule.

EXAMPLE 4 Tablet

(1) compound A 10 mg (2) Pioglitazone hydrochloride 30 mg (3) Lactose 25mg (4) Cornstarch 150 mg (5) Microcrystalline cellulose 30 mg (6)Magnesium stearate 5 mg 1 tablet 250 mg (1), (2), (3), (4) ⅔ of (5) and½ of (6) are admixed and granulated. Thereto are added the remaining (5)and (6), and the mixture is compression formed to give tablets.

EXAMPLE 5 Capsule

(1) Candesartan cilexetil 5 mg (2) Pioglitazone hydrochloride 30 mg (3)Lactose 85 mg (4) Microcrystalline cellulose 70 mg (5) Magnesiumstearate 10 mg 1 capsule 200 mg (1), (2), (3), (4) and ½ of (5) areadmixed and granulated. Thereto is added the remaining (5), and thetotal amount is sealed in a gelatin capsule.

EXAMPLE 6 Tablet

(1) Candesartan cilexetil 10 mg (2) Pioglitazone hydrochloride 30 mg (3)Lactose 25 mg (4) Cornstarch 150 mg (5) Microcrystalline cellulose 30 mg(6) Magnesium stearate 5 mg 1 tablet 250 mg (1), (2), (3), (4) ⅔ of (5)and ½ of (6) are admixed and granulated. Thereto are added the remaining(5) and (6), and the mixture is compression formed to give tablets.

INDUSTRIAL APPLICABILITY

The agent of the present invention shows a superior effect on thesuppression of body weight gain.

For example, when a PPARγ agonist-like substance effective for thetreatment of diabetes and other diseases and the like is administered,the target disease is cured, but the body weight of patients reportedlytends to increase. However, the agent of the present invention cansuppress such a body weight gain in such patients.

1. A method of inhibiting a body weight gain in a mammal comprisingadministering a composition consisting of an effective amount of2-ethoxy-1-[[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylicacid, a prodrug thereof or a salt thereof, an effective amount of aPPARγ agonist-like substance, and a pharmaceutically acceptable carrierin combination to the mammal.
 2. The method of claim 1 wherein the PPARδagonist-like substance is pioglitazone.